Black Phosphorus Quantum Dots Cause Nephrotoxicity in Organoids, Mice, and Human Cells
Black Phosphorus Quantum Dots Cause Nephrotoxicity in Organoids, Mice, and Human Cells
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DOI：
10.1002/smll.202001371
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发表时间：
2020-04-27
期刊：
影响因子：
13.3
通讯作者：
Zuo, Zhenghong
中科院分区：
文献类型：
--
作者：
He, Chengyong;Ruan, Fengkai;Zuo, Zhenghong
量子点（QD）在照明、工程和生物医学中具有许多潜在的应用。由于QD的超小尺寸，QD主要通过肾脏排泄;因此，肾脏是QD毒性的靶器官。本文建立了一个类器官筛选平台，并用于研究量子点的肾毒性。类器官是从单分散微流体基质胶液滴中模板化的，并且被发现在群体内的组织结构和功能重演中是均匀的，并且适合于毒性剂量的定量筛选。肾脏类器官被证明比2D培养的细胞系显示出更高的灵敏度。与含金属的量子点类似，黑磷（BP）-量子点被发现在肾脏类器官中具有中度毒性。在小鼠和人肾小管上皮细胞中验证了BP-QD的肾毒性。还发现BP-QD引起肾脏中的胰岛素不敏感性和内质网（ER）应激。此外，ER应激相关的IRE 1 α信号传导显示介导由BP-QD引起的肾毒性和胰岛素不敏感性。总之，这项工作证明了使用构建的肾脏类器官作为3D高通量筛选工具来评估纳米安全性，并进一步阐明了BP-QD肾毒性的作用和分子机制。这些发现有望提高BP-QD应用的安全性。
Quantum dots (QDs) have numerous potential applications in lighting, engineering, and biomedicine. QDs are mainly excreted through the kidney due to their ultrasmall sizes; thus, the kidneys are target organs of QD toxicity. Here, an organoid screening platform is established and used to study the nephrotoxicity of QDs. Organoids are templated from monodisperse microfluidic Matrigel droplets and found to be homogeneous in both tissue structure and functional recapitulation within a population and suitable for the quantitative screening of toxic doses. Kidney organoids are proved displaying higher sensitivity than 2D-cultured cell lines. Similar to metal-containing QDs, black phosphorus (BP)-QDs are found to have moderate toxicity in the kidney organoids. The nephrotoxicity of BP-QDs are validated in both mice and human renal tubular epithelial cells. BP-QDs are also found to cause insulin insensitivity and endoplasmic reticulum (ER) stress in the kidney. Furthermore, ER stress-related IRE1 alpha signaling is shown to mediate renal toxicity and insulin insensitivity caused by BP-QDs. In summary, this work demonstrates the use of constructed kidney organoids as 3D high-throughput screening tools to assess nanosafety and further illuminates the effects and molecular mechanisms of BP-QD nephrotoxicity. The findings will hopefully enable improvement of the safety of BP-QD applications.